Download From the Editor Nimesulide Adverse Reactions Reported

ST QUARTER 1998
1 –
–3
1RD
VOLUME 2 – NUMBER 3
From the Editor
In this Issue
In the previous issues we have focused mostly on data ariFrom the Editor
p. 1
Nimesulide:
adverse reactions reported to the CNF
p. 1
Tramadol and risk of addiction
and respiratory depression - changes in the SPC
p. 2
medicines, from the lab professional to the prescribing doctor
Sildenafil:
reported ADRs and safety profile
p. 3
and the patients themselves. In this issue, preliminary safety
Cisapride and arrhythmia - changes in the SPC
p. 4
Drugs under assessment
p. 4
sing from drug safety profile assessments. We have tried to keep
up health professionals with issues that are relevant for their
daily practice, in an attempt to contribute whenever possible
towards our patients’ health protection and prevention of iatrogenic events.
The pharmacovigilance process, however, depends by its
own nature on the active participation of all those who handle
data resulting from spontaneous ADR reports are presented in
respect to two drugs that have lately been under close scrutiny
for diverse reasons – nimesulide and sildenafil. Some doubts
about their safety profiles may be clarified, whilst others will certainly arise. This will hopefully help to make doctors and pharma-
cists more aware of possible ADRs whose reports may shed
more light on current safety concerns.
Nimesulide
Adverse Reactions Reported to the CNF
Nimesulide is a non-steroid anti-inflammatory (NSAID) sulphonanilide whose mechanism of action is characterised by selective inhibition of cyclo-oxigenase 2 (COX2).
This pharmacodynamic profile is compatible with a lower
incidence of adverse GI reactions in comparison with
other NSAIDs, although this has not been clearly
demonstrated.1 Some studies show that the incidence of this
type of ADRs with nimesulide is similar to that of patients treated with a control NSAID. Furthermore, there may appear
endoscopically visible lesions of the gastric mucosa with nimesulide2, and the selectivity of COX2 inhibition may be lost at higher doses.3
The National Pharmacovigilance Centre (CNF) has received,
since 1993, 17 ADR reports ascribed to nimesulide. The most
frequent ones were skin (5) and liver (4) ADRs. Others were:
peripheral oedema (2), stomatitis (2), paresthesia (1),
thrombocytopaenic purpura (1), irritability (1), and headaches/reduced visual acuity (1). No adverse GI reactions
have been reported.
The adverse skin reactions reported included three cases of
rash, one case of urticaria/angioedema, and one case of necrotising fasciitis which evolved to septicaemia and death. Except
for the case of necrotising fasciitis, these ADRs have
been previously described with the administration of nimesulide.
Several cases of necrotising fasciitis are described in association with various NSAIDs, but this association has never been
clearly demonstrated.
Of the hepatic ADRs reported, two cases were compatible
with Reye’s syndrome. They occurred in children and were
both fatal. One case of cholestasis, and another of liver enzyme
FICHA TÉCNICA Director: Dr. António Faria Vaz: Editor: Dr. Rui Pombal: Contributors: Dr.a Anabela Lima (AL),
Dr.a Cristina Rocha (CR), Prof.a Doutora Cristina Sampaio (CS), Dr.a Fátima Vaz (FV), Prof. Doutor Jorge Polónia (JP),
Dr.a M. Rosário Pereira Rosa (RR), Dr. Pedro Marques da Silva (MS), Dr.a Regina Carmona (RC), Prof. Doutor Vasco Maria (VM);
Consultants: Prof. Doutor J. M. G. Toscano Rico; Prof. Doutor Frederico José Teixeira; Prof. Doutor J. M.
Moreira Gonçalves; Prof. Doutor J. M. de Sousa Pinto; Dr. J. C. F. Marinho Falcão; Prof.a Doutora Rosário Brito Correia
Lobato; Publisher: INFARMED – Instituto Nacional da Farmácia e do Medicamento, Parque de
Saúde de Lisboa, Av. Brasil, N.o 53, 1700 Lisboa, Tel. (01) 790 85 00, Fax. (01) 795 91 16, correio electrónico:
[email protected].; Printing: GRÁFICA MAIADOURO; Depósito Legal n.o 115699/97. ISSN 0873-7118.
Print run: 37.750 copies (Portuguese edition).
fatal. Liver enzyme elevation and acute hepatitis in
drugs, is of the utmost importance to make these safety issues
clearer.98.Oct.12
patients on nimesulide are mentioned in the literature. 4,5 In the
FV
elevation and coagulopathy were also reported, the latter being
cases reported to the CNF, all patients were concomitantly
medicated with amoxicillin+clavulanate. Similarly, one of
1
the patients who died of Reye’s syndrome had also been given
lisine salicylate.
2
Although the reporting professionals ascribed a causal relationship to nimesulide, one cannot firmly exclude the direct role
3
of the amoxicillin+clavulanate association in causing liver
damage, whose occurrence has been described with the use of
4
this antibiotic (see Vol.1, n. o 4). On the other hand, it is not
known whether there may be an interaction between nimesulide
and amoxicillin+clavulanate which may potentiate the hepatic
dysfunction induced by any one of these drugs.
Reporting to the CNF all serious ADRs that may be related to
the use of nimesulide given alone or in combination with other
5
Davis R, Brogden RN. Nimesulide. An update of its pharmacodynamic and
pharmacokinetic properties, and therapeutic efficacy. Drugs 1994;
48(3):431-54.
Porto A, Almeida H, Cunha MJ, Macciocchi A. Double-blind study evaluating
by endoscopy the tolerability of nimesulide and diclofenac on the gastric
mucosa in osteoarthritic patients. Eur J Rheumatol Inflamm 1994; 14 (4): 33-8.
Wallace JL, Bak A, McKnight W, Asfaha S, Sharkey KA, MacNaughton WK.
Ciclooxigenase 1 contributes to inflammatory responses in rats and mice:
implications for gastrointestinal toxicity. Gastroenterology 1998; 115 (1):101-9.
Selig J, Liberek C, Kondo Oestreicher M, Desmeules J, Stoller R, Dayer P.
Nimesulid hepatotoxicity. Sixth Annual Meeting - European Society of
Pharmacovigilance. Budapest, September 28-29, 1998.
Van Steenbergen W, Peeters P, De Bondt J, Staessen D, Buscher H,
Laporta T, et al. Nimesulide-induced acute hepatitis: evidence from six
cases. J Hepatol 1998; 29 (1): 135-41.
TRADE MARK NAMES OF NIMESULIDE WITH MARKETING AUTHORISATION
Aulin®; Donulide®; Jabasulide®; Nimed®; Sulimed®
IN
PORTUGAL:
Tramadol and Risk of Addiction and
Respiratory Depression: Changes
in the SPC
Tramadol is a central opioid, codeine-analogue analgesic,
which may be given through the oral, rectal, intramuscular
or intravenous routes, for the treatment of acute, moderate
to severe pain. It is a µ and κ receptor agonist, and is capable of inhibiting noradrenaline re-uptake and of stimulating serotonine release, thus modulating central pain perception and providing a broader anti-nociceptive effect.
Tramadol is, for its most part, metabolised by the liver (under
the control of the polymorph CYP3A4 isoenzyme of cytochrome
P450), originating an active metabolite (M1) with opioid-like
activity. Tramadol is predominantly eliminated through the kidneys, and its active metabolite has an elimination half-life of 6 to
9 hours.
Initially viewed as a central analgesic drug with a lower risk
for addiction and cardiac and respiratory depression, these
safety profile aspects have recently been reassessed.
Tramadol’s Summaries of Product Characteristics (SPC) have
been subjected to some changes, in order to make them more
uniform and to underscore the above aspects.
The chapter on SPECIAL PRECAUTIONS OF USE will now read
as follows:
• Tramadol shows a low potential for causing addiction.
Its prolonged use may be associated with tolerance
and physical and psychological addiction. In patients
prone to drug abuse and addiction, treatment with tramadol should be restricted to short courses, and must
take place under strict medical supervision.
• Tramadol must be used with caution in opioid-sensitive
patients.
• As a pain-killer, tramadol must be used with caution in
opioid-dependent patients , in patients with head
2 Volume 2,
Number 3,
3rd Quarter 1998
trauma, shock, reduced levels of consciousness of uncertain origin, respiratory centre or function disturbances, or
increased intracranial pressure.
• Tramadol is not adequate for the treatment of opioid
withdrawal syndrome. Although it is an opioid agonist, tramadol does not suppress morphine withdrawal
symptoms.
• Seizures have been reported in patients treated with tramadol in the recommended doses. This risk may be
increased when the dose of tramadol exceeds the maximum daily dose (400 mg). Tramadol may increase the
risk of seizures in patients treated with other drugs that
lower the seizure threshold . Epileptic or seizure-prone patients should only be treated with tramadol after its risk-benefit ratio has been duly pondered.
As for UNDESIRABLE EFFECTS, the following aspects should
be noted (among others already highlighted in previous versions
of the SPC):
• Nausea and vertigo were reported frequently (> 10%).
• Vomiting, constipation, sweating, dry mouth, headaches,
and visual disturbances, may occasionally (1-10%) occur.
• Addiction may occur. Withdrawal symptoms similar to
those characteristic of opioid withdrawal may occur,
namely: agitation, anxiety, irritability, insomnia, restlessness, tremor, and GI symptoms.
98.Jul.31
MS
TRADE MARK NAMES OF TRAMADOL WITH MARKETING AUTHORISATION IN PORTUGAL:
Euflore®; Paxilfar®; Theradol®; Tramadol caps®; Tramal®; Travex®.
Sildenafil:
Reported ADRs and Safety Profile
Sildenafil was approved by the FDA in 98-03-27 for the
treatment of erectile dysfunction, based on clinical trials
that included over 3,700 patients. This drug received favourable
appreciation by the EMEA’s CPMP on the 27th of May 1998, and
was approved by the European Committee on the 14th of
September 1998 as a prescription-only medicine.
• Safety data from clinical trials
Sildenafil’s safety profile was assessed in a series of doubleblind, placebo-controlled clinical trials, with a total of 2,722
patients medicated for 6 months, as well as in 10 open-label studies with 2,199 patients treated during one year. The most frequently identified adverse reactions in the pre-marketing phase
were: headaches (16%), flushing (10%), and dyspepsia
(7%). Other reactions described included nasal congestion,
visual disturbances, and diarrhoea.
The adverse effects identified were, in general, mild or
moderate, and of short duration. Discontinuation of the-
reports of serious ADRs and 171 reports of non-serious
events associated with the use of sildenafil. The non-serious
events were mostly reduced (46 cases) or no (27 cases) therapeutic response, and impotence (18 cases). Other frequently reported secondary effects were headaches, visual disturbances, and flushing.
Of the 125 serious cases reported, 115 were deemed
unexpected according to the SPC approved in the USA. These
cases included 35 fatal outcomes, in 17 of which the cause
of death was not known. In the remainder, the cause of death
was stroke (2) or cardiac events.
The non-fatal cases included cardiac manifestations (from myocardial infarct to cardiac arrest and pulmonary
oedema), stroke, disturbances of cardiac rhythm,
hypotension, priapism or prolonged erection, and
visual disturbances (blurring, vitreous haemorrhage, or loss
of vision).
• Conclusions
rapy due to adverse reactions occurred in about 2% of treated
patients.
• Data from ADRs spontaneously reported to the
FDA
From the time the drug was marketed in the USA (March,
1998) to the end of June, more than 2.7 million prescriptions of sildenafil were dispensed. During this period, 123
cases of patients that died supposedly after taking sildenafil
were reported to the FDA. In 30 of these patients (24%), report
reliability was questionable, in that the source was not identifiable, information had been passed on to third parties who
had heard of those cases, or who had known about them
through non-medical press. Additionally, in 12 patients, the
reporting person said that the use of sildenafil had not been
confirmed.
The FDA analysed in further detail the reports pertaining to
the 69 patients who were proven to have died after taking sildenafil. Their average age was 64 years (29-87 years). In 21
patients, the cause of death was not mentioned, or was unknown. Of the remainder, two had a stroke, and 46 had cardiac
events. In 12 patients, nitroglycerine or other nitrate-containing
The analysis of the safety data emerging from clinical trials
and spontaneous ADR reports in patients medicated with sildenafil allows one to draw the following conclusions:
• There does not seem to be a higher frequency of adverse
reactions in the post-marketing phase, when compared
with the research phase.
• As for unexpected adverse events, and especially in what
concerns fatal outcomes, many such occurrences
could be considered to be expected, independently of sildenafil, given the age of the patients and the diseases
from which they suffered (heart disease, diabetes, high
blood pressure).
• Virtually all reported deaths occurred in patients with a
contraindication to sildenafil, namely high coronary
risk and/or nitrate therapy. These contraindications
and precautions are, in any case, included in the approved SPC.
• Within this context, the currently available data pertaining
to sildenafil and emerging from spontaneous ADR reports
do not alter the currently known safety profile of this drug.
98.Oct.12
medication had been administered. This association with sildeVM
nafil is contraindicated. In 51 of the 69 patients, one or more
coronary risk factors were identified (high blood pressure,
hypercholesterolaemia, smoking, diabetes, obesity, or past cardiac events).
• Data from spontaneous reports to the holder of
marketing authorisation (Pfizer)
The first safety report, corresponding to the period from the
27th of March (FDA approval) to the 15th of June, was made
available to the EMEA and to the member-states in the beginning of July. During that period, Pfizer received 125 spontaneous
TRADE MARK NAMES OF SILDENAFIL WITH MARKETING AUTHORISATION IN PORTUGAL:
Patrex®; Viagra®.
If you suspect that your patient might have
symptoms and/or signs of an adverse drug reaction,
and especially if the event is unexpected, incapacitating or severe - REPORT IT!
Volume 2,
Number 3,
3rd Quarter 1998 3
Cisapride and Arrhythmia
Changes in the SPC
Cisapride is a gastrointestinal prokinetic drug that has been
under review by the CNF in what concerns its safety of use in
children and its potential to induce cardiac arrhythmia (see Vol. 1, N.o 4).
Recent experimental evidence suggests that cisapride in
therapeutic concentrations has direct electrophysiologic effects
on the ion flows responsible for cardiac depolarisation. This may
explain the rare cases of ventricular arrhythmia and QT-interval
prolongation reported internationally. In most cases, the patients
also had other risk factors for arrhythmia, or were simultaneously
medicated with drugs which inhibit cytochrome P450 or prolong
the QT interval themselves.
The CNF has deemed it necessary to change the SPC of all
medicines whose active substance is cisapride. Among others,
the following data have been included in their corresponding
chapters:
–
–
–
–
Renal failure (especially patients on chronic dialysis).
Significant obstructive airways disease.
Respiratory failure.
Conditions associated with QT-interval prolongation
(such as congenital prolonged QT syndrome, prolonged QT interval associated with diabetes mellitus, association with drugs known to cause QT-interval prolongation).
– History of known heart disease (including severe ventricular arrhythmia, 2nd or 3rd degree AV block, congestive heart failure, ischaemic heart disease).
In patients who have or are suspected to have the abovementioned risk factors, the risk-benefit ratio should be
carefully pondered before starting therapy with cisapride.
98.Oct.08
• CONTRAINDICATIONS
RR
– Simultaneous oral or parentheral administration of
potent CYP3A4 inhibitors such as: oral antifungal
agents; macrolide antibiotics such as erythromycin, clarithromycin, or troleandromycin; HIV protease
inhibitors; nefazodone.
– Premature new-borns (less than 36 weeks’ gestation) from birth to three months of age.
• WARNINGS
AND
SPECIAL PRECAUTIONS
OF
USE
It is advisable to avoid the use of cisapride in patients with
the following risk factors for cardiac arrhythmia:
– Non-corrected water and electrolyte imbalances (potassium/magnesium), such as those occurring in patients
who take potassium-depleting diuretics, or insulin in
acute settings.
TRADE MARK NAMES OF CISAPRIDE WITH MARKETING AUTHORISATION IN PORTUGAL:
Aceleran®; Cismotil®; Clotioride®; Coordinax®; Dispepci®; Prepulsid®.
All ADR reports get fully grounded, individualised,
and strictly confidential feedback from the National
Pharmacovigilance Centre.
Drugs under assessment*
• albumin • amoxicillin + clavulanate • anti-histamines (non-sedative) • appetite suppressants • aprotinine
• association of caffeine with salicylates, pyrazolone, paracetamol • bromocriptine • camphor • carvedilol •
cisapride • clozapine • contrast media (high osmolarity) • corticosteroids (inhaled) • dipiridamole • droperidol • glimepiride • glipizide • halogenated anaesthetics • hormonal replacement therapy • isotretinoin •
ketorolac • meloxicam • methadone • montelukast • nicotine • nimesulide • nucleosides (analogues) •
oral contraceptives • pancreatine • phenilpropalamine + pseudo-ephedrine • piroxicam • protease inhibitors • selective serotonine re-uptake inhibitors (SSRIs) • sertindole • sildenafil • tamoxifen • ticlopidine •
tramadol • vigabatrim • zafirlukast
* The drugs in this issue are in bold-faced type. This is a list of the medicines currently under special assessment (monitoring/information) at the National Pharmacovigilance Centre. These drugs, however, do not necessarily correspond to products with problems
that may imply some change in their SPCs or marketing authorisations.
4 Volume 2,
Number 3,
3rd Quarter 1998